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Black Box Warning

FETAL TOXICITY

See full prescribing information for complete boxed warning.

When pregnancy is detected, discontinue benazepril hydrochloride as soon as possible.

Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Hypertension

Dosing Information

Initial dose (not receiving a diuretic): Benazepril 10 mg PO qd

Initial dose (concurrent diuretic use): the diuretic should be discontinued 2 to 3 days prior to initiating Benazepril to reduce the likelihood of hypotension. If blood pressure is not controlled with Benazepril alone, diuretic should be resumed and Benazepril 5 mg PO qd should be used.

The divided regimen was more effective in controlling trough (pre-dosing) blood pressure than the same dose given as a once-daily regimen. Dosage adjustment should be based on measurement of peak (2-6 hours after dosing) and trough responses. If a once-daily regimen does not give adequate trough response, an increase in dosage or divided administration should be considered.

For pediatric patients who cannot swallow tablets, or for whom the calculated dosage (mg/kg) does not correspond to the available tablet strengths for Benazepril, follow the suspension preparation instructions to administer Benazepril HCl as a suspension.

Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with angiotensin-converting enzyme inhibitors. In U.S. clinical trials, symptoms consistent with angioedema were seen in none of the subjects who received placebo and in about 0.5% of the subjects who received Benazepril. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, treatment with Benazepril should be discontinued and appropriate therapy instituted immediately. Where there is involvement of the tongue, glottis, or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine injection 1:1000 (0.3 mL to 0.5 mL) should be promptly administered.

Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to nonblacks.

Hypotension

Benazepril can cause symptomatic hypotension. Like other ACE inhibitors, Benazepril has been only rarely associated with hypotension in uncomplicated hypertensive patients. Symptomatic hypotension is most likely to occur in patients who have been volume-and/or salt-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Volume-and/or salt-depletion should be corrected before initiating therapy with Benazepril.

If hypotension occurs, the patient should be placed in a supine position, and, if necessary, treated with intravenous infusion of physiological saline. Benazepril treatment usually can be continued following restoration of blood pressure and volume.

In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Benazepril, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Benazepril for hypotension, oliguria, and hyperkalemia.

No teratogenic effects of Benazepril were seen in studies of pregnant rats, mice, and rabbits. On a mg/m2 basis, the doses used in these studies were 60 times (in rats), 9 times (in mice), and more than 0.8 times (in rabbits) the maximum recommended human dose (assuming a 50-kg woman). On a mg/kg basis these multiples are 300 times (in rats), 90 times (in mice), and more than 3 times (in rabbits) the maximum recommended human dose.

Adverse Reactions

Clinical Trials Experience

Benazepril has been evaluated for safety in over 6000 patients with hypertension; over 700 of these patients were treated for at least one year. The overall incidence of reported adverse events was comparable in Benazepril and placebo patients.

The reported side effects were generally mild and transient, and there was no relation between side effects and age, duration of therapy, or total dosage within the range of 2 to 80 mg. Discontinuation of therapy because of a side effect was required in approximately 5% of U.S. patients treated with Benazepril and in 3% of patients treated with placebo.

The most common reasons for discontinuation were headache (0.6%) and cough (0.5%)

The side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled trials in more than 1% of patients treated with Benazepril are shown below.

Other adverse experiences reported in controlled clinical trials (in less than 1% of Benazepril patients or with less than 1% difference in incidence between Benazepril or placebo treatment), and rarer events seen in post-marketing experience, include the following (in some, a causal relationship to drug use is uncertain):

Decreases in hemoglobin (a low value and a decrease of 5 g/dL) were rare, occurring in only 1 of 2,014 patients receiving Benazepril alone and in 1 of 1,357 patients receiving Benazepril plus a diuretic. No U.S. patients discontinued treatment because of decreases in hemoglobin.

Postmarketing Experience

Drug Interactions

Diuretics

Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with Benazepril. The possibility of hypotensive effects with Benazepril can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with Benazepril. If this is not possible, the starting dose should be reduced.

In rare cases, diabetic patients receiving an ACE inhibitor (including Benazepril) concomitantly with insulin or oral anti-diabetics may develop hypoglycemia. Such patients should therefore be advised about the possibility of hypoglycemic reactions and should be monitored accordingly.

In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Benazepril, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Benazepril for hypotension, oliguria, and hyperkalemia.

No teratogenic effects of Benazepril were seen in studies of pregnant rats, mice, and rabbits. On a mg/m2 basis, the doses used in these studies were 60 times (in rats), 9 times (in mice), and more than 0.8 times (in rabbits) the maximum recommended human dose (assuming a 50-kg woman). On a mg/kg basis these multiples are 300 times (in rats), 90 times (in mice), and more than 3 times (in rabbits) the maximum recommended human dose.

Labor and Delivery

Nursing Mothers

Minimal amounts of unchanged Benazepril and of benazeprilat are excreted into the breast milk of lactating women treated with Benazepril. A newborn child ingesting entirely breast milk would receive less than 0.1% of the mg/kg maternal dose of Benazepril and benazeprilat.

Pediatric Use

Neonates with a history of in utero exposure to Benazepril

If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Benazepril, which crosses the placenta, can theoretically be removed from the neonatal circulation by these means; there are occasional reports of benefit from these maneuvers with another ACE inhibitor, but experience is limited.

The antihypertensive effects of Benazepril have been evaluated in a double-blind study in pediatric patients 7 to 16 years of age . The pharmacokinetics of Benazepril have been evaluated in pediatric patients 6 to 16 years of age . Benazepril was generally well tolerated and adverse effects were similar to those described in adults.The long-term effects of Benazepril on growth and development have not been studied. Infants below the age of 1 year should not be given Benazepril because of the risk of effects on kidney development.

Treatment with Benazepril is not recommended in pediatric patients less than 6 years of age , and in children with glomerular filtration rate <30 mL/min as there are insufficient data available to support a dosing recommendation in these groups.

Geriatric Use

Of the total number of patients who received Benazepril in U.S. clinical studies of Benazepril, 18% were 65 or older while 2% were 75 or older. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Benazepril and benazeprilat are substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of carcinogenicity was found when Benazepril was administered to rats and mice for up to two years at doses of up to 150 mg/kg/day. When compared on the basis of body weights, this dose is 110 times the maximum recommended human dose. When compared on the basis of body surface areas, this dose is 18 and 9 times (rats and mice, respectively) the maximum recommended human dose (calculations assume a patient weight of 60 kg).

No mutagenic activity was detected in the Ames test in bacteria (with or without metabolic activation), in an in vitro test for forward mutations in cultured mammalian cells, or in a nucleus anomaly test.

In doses of 50-500 mg/kg/day (6-60 times the maximum recommended human dose based on mg/m2 comparison and 37-375 times the maximum recommended human dose based on a mg/kg comparison), Benazepril had no adverse effect on the reproductive performance of male and female rats.

Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Surgery/Anesthesia

In patients undergoing surgery or during anesthesia with agents that produce hypotension, Benazepril will block the angiotensin II formation that could otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion.

Administration and Monitoring

Administration

Oral

Preparation of suspension (for 150 mL of a 2 mg/mL suspension)

Add 75 mL of Ora-Plus® oral suspending vehicle to an amber polyethylene terephthalate (PET) bottle containing fifteen Benazepril 20 mg tablets, and shake for at least 2 minutes. Allow the suspension to stand for a minimum of 1 hour. After the standing time, shake the suspension for a minimum of 1 additional minute. Add 75 mL of Ora-Sweet® oral syrup vehicle to the bottle and shake the suspension to disperse the ingredients. The suspension should be refrigerated at 2-8°C (36-46°F) and can be stored for up to 30 days in the PET bottle with a child-resistant screw-cap closure. Shake the suspension before each use.

Monitoring

Geriatric Use

Benazepril and benazeprilat are substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Overdose

Patients should be closely monitored for blood pressure and clinical symptoms. Supportive management should be employed to ensure adequate hydration and to maintain systemic blood pressure.

In rare cases, diabetic patients receiving an ACE inhibitor (including Benazepril) concomitantly with insulin or oral anti-diabetics may develop hypoglycemia. Such patients should therefore be advised about the possibility of hypoglycemic reactions and should be monitored accordingly.

IV Compatibility

Overdosage

Acute Overdose

Signs and Symptoms

Human overdoses of Benazepril have not been reported, but the most common manifestation of human Benazepril overdosage is likely to be hypotension, which can be associated with electrolyte disturbances and renal failure.

Management

Laboratory determinations of serum levels of Benazepril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of Benazepril overdose.

No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of Benazepril and its metabolites. Benazepril is only slightly dialyzable, but dialysis might be considered in overdosed patients with severely impaired renal function (see Warnings).

Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of Benazepril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of Benazepril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat Benazepril overdose by infusion of normal saline solution.

Patients should be closely monitored for blood pressure and clinical symptoms. Supportive management should be employed to ensure adequate hydration and to maintain systemic blood pressure.

In the case of marked hypotension, physiological saline solution should be administered intravenously; depending on the clinical situation the use of vasopressors (e.g., catecholaminesi.v.) may be considered.

Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. Hypertensive patients treated with Benazepril alone for up to 52 weeks had elevations of serum potassium of up to 0.2 mEq/L. Similar patients treated with Benazepril and hydrochlorothiazide for up to 24 weeks had no consistent changes in their serum potassium.

ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of Benazepril remains to be elucidated.

Benazepril hydrochloride is a white to off-white crystalline powder, soluble (>100 mg/mL) in water, in ethanol, and in methanol. Its chemical name is benazepril 3-[[1-(ethoxy-carbonyl)-3-phenyl-(1S)-propyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-(3S)-benzazepine-1-acetic acid monohydrochloride.

Its empirical formula is C24H28N2O5•HCl, and its molecular weight is 460.96.

Pharmacodynamics

Single and multiple doses of 10 mg or more of Benazepril cause inhibition of plasma ACE activity by at least 80%-90% for at least 24 hours after dosing. Pressor responses to exogenous angiotensin I were inhibited by 60%-90% (up to 4 hours post-dose) at the 10-mg dose.

Pharmacokinetics

Following oral administration of Benazepril, peak plasma concentrations of Benazepril are reached within 0.5-1.0 hours. The extent of absorption is at least 37% as determined by urinary recovery and is not significantly influenced by the presence of food in the GI tract.

Cleavage of the ester group (primarily in the liver) converts Benazepril to its active metabolite, benazeprilat. Peak plasma concentrations of benazeprilat are reached 1-2 hours after drug intake in the fasting state and 2-4 hours after drug intake in the nonfasting state. The serum protein binding of Benazepril is about 96.7% and that of benazeprilat about 95.3%, as measured by equilibrium dialysis; on the basis of in vitro studies, the degree of protein binding should be unaffected by age, hepatic dysfunction, or concentration (over the concentration range of 0.24-23.6 µmol/L).

Benazepril is almost completely metabolized to benazeprilat, which has much greater ACE inhibitory activity than Benazepril, and to the glucuronide conjugates of Benazepril and benazeprilat. Only trace amounts of an administered dose of Benazepril can be recovered in the urine as unchanged Benazepril, while about 20% of the dose is excreted as benazeprilat, 4% as benazepril glucuronide, and 8% as benazeprilat glucuronide.

The kinetics of Benazepril are approximately dose-proportional within the dosage range of 10-80 mg.

In adults, the effective half-life of accumulation of benazeprilat following multiple dosing of benazepril hydrochloride is 10-11 hours. Thus, steady-state concentrations of benazeprilat should be reached after 2 or 3 doses of benazepril hydrochloride given once daily.

The kinetics did not change, and there was no significant accumulation during chronic administration (28 days) of once-daily doses between 5 mg and 20 mg. Accumulation ratios based on AUC and urinary recovery of benazeprilat were 1.19 and 1.27, respectively.

Benazepril and benazeprilat are cleared predominantly by renal excretion in healthy subjects with normal renal function. Nonrenal (i.e., biliary) excretion accounts for approximately 11%-12% of benazeprilat excretion in healthy subjects. In patients with renal failure, biliary clearance may compensate to an extent for deficient renal clearance.

When dialysis was started 2 hours after ingestion of 10 mg of Benazepril, approximately 6% of benazeprilat was removed in 4 hours of dialysis. The parent compound, Benazepril, was not detected in the dialysate.

In pediatric patients, (N=45) hypertensive, age 6 to 16 years, given multiple daily doses of Benazepril (0.1 to 0.5 mg/kg), the clearance of benazeprilat for children 6 to 12 years old was 0.35 L/hr/kg, more than twice that of healthy adults receiving a single dose of 10 mg (0.13 L/hr/kg). In adolescents, it was 0.17 L/hr/kg, 27% higher than that of healthy adults. The terminal elimination half-life of benazeprilat in pediatric patients was around 5 hours, one-third that observed in adults.

Nonclinical Toxicology

Clinical Studies

Hypertension

Adult

In single-dose studies, Benazepril lowered blood pressure within 1 hour, with peak reductions achieved 2-4 hours after dosing. The antihypertensive effect of a single dose persisted for 24 hours. In multiple-dose studies, once-daily doses of 20-80 mg decreased seated pressure (systolic/diastolic) 24 hours after dosing by about 6-12/4-7 mmHg. The trough values represent reductions of about 50% of that seen at peak.

Four dose-response studies using once-daily dosing were conducted in 470 mild-to-moderate hypertensive patients not using diuretics. The minimal effective once-daily dose of Benazepril was 10 mg; but further falls in blood pressure, especially at morning trough, were seen with higher doses in the studied dosing range (10-80 mg). In studies comparing the same daily dose of Benazepril given as a single morning dose or as a twice-daily dose, blood pressure reductions at the time of morning trough blood levels were greater with the divided regimen.

The antihypertensive effects of Benazepril were not appreciably different in patients receiving high- or low-sodium diets.

In normal human volunteers, single doses of Benazepril caused an increase in renal blood flow but had no effect on glomerular filtration rate.

Pediatric

In a clinical study of 107 pediatric patients, 7 to 16 years of age, with either systolic or diastolic pressure above the 95th percentile, patients were given 0.1 or 0.2 mg/kg then titrated up to 0.3 or 0.6 mg/kg with a maximum dose of 40 mg once daily. After four weeks of treatment, the 85 patients whose blood pressure was reduced on therapy were then randomized to either placebo or Benazepril and were followed up for an additional two weeks. At the end of two weeks, blood pressure (both systolic and diastolic) in children withdrawn to placebo rose by 4 to 6 mmHg more than in children on Benazepril. No dose-response was observed for the three doses.

How Supplied

Benazepril is available in tablets of 5 mg, 10 mg, 20 mg, and 40 mg, packaged with a desiccant in bottles of 100 tablets.

Each tablet is imprinted with Benazepril on one side and the tablet strength (“5,” “10,” “20,” or “40”) on the other.

Patient Information

Patient Information from FDA

Pregnancy

Female patients of childbearing age should be told about the consequences of exposure to Benazepril during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.

Angioedema

Angioedema, including laryngeal edema, can occur at any time with treatment with ACE inhibitors. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, eyes, lips, or tongue, or difficulty in breathing) and to take no more drug until they have consulted with the prescribing physician.

Symptomatic Hypotension

Patients should be cautioned that lightheadedness can occur, especially during the first days of therapy, and it should be reported to the prescribing physician. Patients should be told that if syncope occurs, Benazepril should be discontinued until the prescribing physician has been consulted.